The rapid increase of knowledge in recent years about the molecular and cellular bases of immune regulation, particularly at the level of T cell responses, provides a new arsenal of immunotherapeutic approaches including the development of anti-tumor vaccines. Certain monoclonal antibodies were shown to have immunomodulatory activity including the ability to bind determinants on the surface of T cells and to induce proliferation, activation, maturation or differentiation of these cells.
BAT (also referred to as mBAT-1 or BAT-1) is a murine monoclonal antibody generated against a membrane preparation of a Burkitt lymphoma cell line (Daudi) that was shown to exhibit antitumor and immunostimulatory effects towards various types of tumors (Hardy et al., 2001, Int. J. Oncol. 19:897). This monoclonal antibody was initially disclosed in U.S. Pat. No. 5,897,862 to Hardy et al. BAT-1 is secreted by the hybridoma cell line having CNCM Accession No. I-1397. The immunomodulatory effect of murine BAT was studied also in vitro. Murine BAT activates CD4+ T cells and induces the secretion of IFN-γ from these cells (Hardy et al., 2000, Int. Immunol. 12:1623 and Quaglino E. et al., 2005, Vaccine 9:23(25):3280-7). In addition, it was found that BAT triggers the proliferation of T cells and increases their cytolytic activity (Hardy, B. et al., 1997, Hum. Antibodies, 8:95).
The polynucleotide and amino-acid sequences of murine BAT are disclosed in WO 00/58363, to Hardy et al., and U.S. Pat. No. 7,695,715.
A number of humanized monoclonal antibodies (mAbs) based on murine BAT are disclosed in U.S. Pat. No. 7,332,582, the contents of which are incorporated herein by reference. In particular embodiments of U.S. Pat. No. 7,332,582, the humanized monoclonal antibodies comprise a light chain variable region selected from SEQ ID NO: 1-4 (denoted BATRKD, BATRKA, BATRKB and BATRKC, respectively) and a heavy chain variable region selected from SEQ ID NO: 5-9 (denoted BATRHC, BATRHA, BATRHB, BATRHD and BATRHE, respectively). The amino acid sequence of the light and heavy chain antibody variants are depicted in Table 1 herein below. The residues which differ in said variable regions are depicted with a gray background (positions 2, 30, 69, 77, 97 and 98 of the light region and positions 35, 69, 70 and 71 of the heavy chain).
According to U.S. Pat. No. 7,332,582, the humanized monoclonal BAT antibodies appear to induce a greater antitumor effect than those induced by the parent murine BAT antibody. Among various model systems tested, the BAT antitumor activity was studied in SCID (severe combined immunodeficiency disease) mice, beige mice that are deficient in NK cells and nude mice that are deficient in T cells (Hardy, B., 1997, Proc. Natl. Acad. Sci. USA 94:5756). All mice were injected intravenously with murine B16 melanoma cells that subsequently developed tumors in the lungs. BAT antibodies exerted an antitumor effect only in SCID mice that were engrafted with either murine or human lymphocytes. In the athymic nude mice and the beige mice BAT antibodies exerted an antitumor activity, though this activity was less effective as compared to the antitumor activity of BAT antibodies in the wild-type mice.
It should be borne in mind that BAT antibodies are not expected to target the tumor cells themselves but rather the immune-functioning cells of the subject or patient, in order to modulate the immune response in a beneficial way.
Berger et al. (2008) discloses administration of the humanized monoclonal antibody CT-011, which is based on mBAT-1, to patients with advanced hematologic malignancies, and associated pharmacokinetics (Berger et al. Clin. Cancer Res. 2008; 14(10) May 15, 2008).
WO 09/101611 relates to methods for inhibiting tumor growth, increasing survival of a subject having a tumor and inducing protection against tumor recurrence in a mammal, comprising administering a humanized monoclonal antibody comprising CDR regions derived from the murine monoclonal antibody designated mBAT-1, in combination with at least one chemotherapeutic agent.
Nowhere in the background art is it taught or suggested that use of a humanized mBAT-1 monoclonal antibody comprising at least one site specific amino acid modification will be advantageous for the therapy of a variety of indications, particularly in the treatment of cancer and immuno-deficiency related diseases and disorders.